rs201629827
Positions:
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP6BS1
The NM_001382391.1(CSPP1):āc.3296A>Gā(p.Glu1099Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000663 in 1,613,646 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: š 0.000066 ( 0 hom., cov: 32)
Exomes š: 0.000066 ( 0 hom. )
Consequence
CSPP1
NM_001382391.1 missense
NM_001382391.1 missense
Scores
2
7
7
Clinical Significance
Conservation
PhyloP100: 4.36
Genes affected
CSPP1 (HGNC:26193): (centrosome and spindle pole associated protein 1) This gene encodes a centrosome and spindle pole associated protein. The encoded protein plays a role in cell-cycle progression and spindle organization, regulates cytokinesis, interacts with Nephrocystin 8 and is required for cilia formation. Mutations in this gene result in primary cilia abnormalities and classical Joubert syndrome. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Apr 2014]
ARFGEF1 (HGNC:15772): (ADP ribosylation factor guanine nucleotide exchange factor 1) ADP-ribosylation factors (ARFs) play an important role in intracellular vesicular trafficking. The protein encoded by this gene is involved in the activation of ARFs by accelerating replacement of bound GDP with GTP. It contains a Sec7 domain, which may be responsible for guanine-nucleotide exchange activity and also brefeldin A inhibition. [provided by RefSeq, Aug 2011]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -3 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP6
?
Variant 8-67190725-A-G is Benign according to our data. Variant chr8-67190725-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 510229.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=2}.
BS1
?
Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0000664 (97/1461410) while in subpopulation MID AF= 0.00503 (29/5764). AF 95% confidence interval is 0.0036. There are 0 homozygotes in gnomad4_exome. There are 55 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CSPP1 | NM_001382391.1 | c.3296A>G | p.Glu1099Gly | missense_variant | 29/31 | ENST00000678616.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CSPP1 | ENST00000678616.1 | c.3296A>G | p.Glu1099Gly | missense_variant | 29/31 | NM_001382391.1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000723 AC: 11AN: 152118Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000561 AC: 14AN: 249516Hom.: 0 AF XY: 0.0000739 AC XY: 10AN XY: 135372
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GnomAD4 exome AF: 0.0000664 AC: 97AN: 1461410Hom.: 0 Cov.: 30 AF XY: 0.0000756 AC XY: 55AN XY: 727052
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GnomAD4 genome ? AF: 0.0000657 AC: 10AN: 152236Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74444
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Joubert syndrome 21 Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jun 23, 2022 | This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 1094 of the CSPP1 protein (p.Glu1094Gly). This variant is present in population databases (rs201629827, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with CSPP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 510229). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Likely benign, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | Aug 07, 2018 | - - |
Congenital ptosis;C0557874:Global developmental delay;C1840379:Cerebellar vermis hypoplasia;C1849075:Relative macrocephaly;C1858120:Generalized hypotonia;C3489733:Oculomotor apraxia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Personalized Medicine, Children's Hospital Los Angeles | - | - - |
CSPP1-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 23, 2024 | The CSPP1 c.3281A>G variant is predicted to result in the amino acid substitution p.Glu1094Gly. This variant was reported as a heterozygous variant of uncertain significance with no second hit, in an individual diagnosed with Joubert syndrome (Ji et al. 2019. PubMed ID: 30755392). In ClinVar this alteration has conflicting classifications of uncertain and likely benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/510229/evidence/ļ»æ). This variant is reported in 0.0098% of alleles in individuals of South Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Dec 04, 2020 | This variant is associated with the following publications: (PMID: 25616960, 30755392) - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Pathogenic
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D
M_CAP
Benign
D
MetaRNN
Uncertain
T;T
MetaSVM
Benign
T
MutationTaster
Benign
D;D;D;D
PrimateAI
Benign
T
PROVEAN
Uncertain
D;D
REVEL
Benign
Sift
Pathogenic
D;D
Sift4G
Uncertain
D;D
Polyphen
D;D
Vest4
MVP
MPC
ClinPred
T
GERP RS
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at